Cardiac Plexus Research Articles

Thunderclap headache as the main symptom of an acute aortic dissection type A

A 67-year-old Caucasian woman presented to our emergency department after the sudden onset of thunderclap headache. The pain was localized ubiquitously in the whole head with a maximum in the visceral cranium and described by the patient as of a knife-stabbing character. A loss of consciousness did not occur. The patient reported on a short-lasting episode of mainly motor aphasia immediately after the onset of the headache. The patient had no history of migraine or other forms of headache and was not taking any medication. The neurological and physical examination was unremarkable. A computer tomography (CT) of the brain showed no signs of intracerebral haemorrhage. A lumbar puncture was declined by the patient. We decided to conduct a CTangiography to detect a possible aneurysm of the intracranial vessels. The CT-examination even included a part of the ascending aorta and the aortic arch to detect a possible dissection of the proximal vertebral arteries. The CT showed a Stanford type A acute aortic dissection (Fig. 1). Furthermore the CT also showed an affection of the proximal part of the supra-aortic vessels (Fig. 2). Confronted with the radiological diagnosis, the patient reported on an aortic aneurysm which had been diagnosed approximately 6 months before. The patient did not show any of the typical symptoms or complications of an acute aortic dissection type A such as pain between the scapulae, the chest, the throat, the abdomen, dyspnoea, heart rate deficits, hypotension and shock, seizures or paresis in the clinical course at all. Subsequent cardiac surgery was conducted successfully. The patient survived without any impairment. Stanford type A acute aortic dissection presenting with headache has been reported before [1–3]. In contrast to the cases published before, headache was, apart from a doubtful short episode of motor aphasia, the only symptom of a Stanford type A acute aortic dissection in the present case. Differential diagnostic causes for the occurrence of thunderclap headache include subarachnoidal haemorrhage, intracerebral haemorrhage, reversible cerebral vasoconstriction syndrome, cerebral venous sinus thrombosis, and dissections of the extracranial vessels [4–6]. Though lacking the examination of cerebrospinal fluid, a subarachnoidal haemorrhage as the underlying cause of the thunderclap headache is not likely regarding the clinical course. Cerebral angiography as well as a doppler and duplex sonographical examination showed no signs of reversible cerebral vasoconstriction syndrome or cerebral venous sinus thrombosis. The clinical course with no other occurrence of thunderclap headache during almost a year after the present incident argues that a reversible cerebral vasoconstriction is also unlikely. A dissection of the proximal extracranial arteries accompanying the aortic dissection could be shown via CT-angiography. A possible explanation of the pain sensation might be the mechanical irritation or vasa nervorum occlusion of the cardiac plexus and the internal carotid plexus with its sympathetic nerve tract projection to the ciliary ganglion and pterygopalatine ganglion. The absence of any cardiovascular reflexes or cardiac pain during clinical observation might be due to the fact H. Rust (&) H. Kimmig Clinic of Neurology, Schwarzwald Baar Klinikum, Rontgenstr. 20, 78054 Villingen-Schwenningen, Germany e-mail: heiko.rust@googlemail.com

Morphology of sympathetic chain in Saguinus niger

Saguinus niger popularly known as Sauim, is a Brazilian North primate. Sympathetic chain investigation would support traumatic and/or cancer diagnosis which are little described in wild animals. The aim of this study was to describe the morphology and distribution of sympathetic chain in order to supply knowledge for neurocomparative research. Three female young animals that came death by natural causes were investigated. Animals were fixed in formaldehyde 10% and dissected along the sympathetic chain in neck, thorax and abdomen. Cranial cervical ganglion was located at the level of carotid bifurcation, related to carotid internal artery. In neck basis the vagosympathetic trunk divides into the sympathetic trunk and the parasympathetic vagal nerve. Sympathetic trunk ran in dorsal position and originated the stellate ganglia, formed by the fusion of caudal cervical and first thoracic ganglia. Vagal trunk laid ventrally to heart and formed the cardiac plexus. In abdomen, on the right side, were found the celiac ganglion and cranial mesenteric ganglion; in the left side these ganglia were fusioned into the celiac-mesenteric ganglion displaced closely to the celiac artery. In both sides, the caudal mesenteric ganglion was located near to the caudal mesenteric artery.

Effect of Epivascular Cardiac Autonomic Nerve Stimulation on Cardiac Function

The cardiac plexus contains sympathetic and parasympathetic cardiac nerves. Our goal was to assess the hemodynamic and functional effects of stimulating the cardiac autonomic nervous system (CANS) at the epivascular surfaces of the cardiac plexus. Although CANS therapy to modulate cardiovascular function has drawn widespread interest, research has focused only on stimulating parasympathetic or sympathetic nerves, not both at once. Using general anesthesia and an open-chest surgical procedure, 12 dogs received epivascular stimulation of the cardiac plexus. A bipolar electrode was placed between the right pulmonary artery (PA) and the ascending aorta, with the stimulation frequency/pulse width held constant (20 Hz/4 ms) and the voltage varied (10-50 V). Left ventricular (LV) pressure-volume loops and hemodynamic data were recorded with and without stimulation. In all dogs, aortic and LV systolic pressures, maximum rate of change of LV pressure, and LV stroke work increased (p<0.0001), as did cardiac output (2.9±1.0-0.4±1.0 L/min; p=0.001), end-systolic elastance (1.2±0.4-1.5±0.5 mm Hg/mL; p=0.0001), preload recruitable stroke work (30.1±11.0-39.3±7.8 mm Hg; p=0.003), and LV ejection fraction (p=0.012). Systemic vascular resistance increased slightly (p=0.04), and pulmonary vascular resistance decreased (p=0.01). Mean heart rate and pulmonary arterial, central venous, and left atrial pressures remained unchanged (p>0.1). In contrast to inotropic drugs, epivascular CANS stimulation induced a significant and selective increase in LV contractility with no increase in heart rate.

Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease

Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (∼20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg·kg(-1)·day(-1)) or vehicle, for a total of 6-7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that β-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the β-receptors were more influential on remodeling during dynamic disease progression.

The effect of celiac plexus block on heart rate variability

Celiac plexus block (CPB) can be used for treating intra-abdominal visceral pain syndromes. The celiac plexus is the largest plexus of the sympathetic nervous system. Several nerve blocks have a marked effect on autonomic nervous activity. Furthermore, stellate ganglion block changes cardiac autonomic nervous activity. Thus, CPB could influence the sympathetic activity of the cardiac plexus. The aim of the present study was to see whether CPB modulated heart rate variability (HRV) in patients with pancreatic cancer. Twelve patients received neurolytic CPB using 14 ml absolute alcohol. Data recorded in a palm-sized electrocardiographic unit were analyzed for HRV. CPB using a neurolytic solution did not induce any significant changes in the low-frequency (LF)/high-frequency (HF) ratio of HRV (LF/HF, P = 0.4642). Furthermore, the procedure did not induce any significant changes in blood pressure (systolic, P = 0.5051; diastolic, P = 0.5180). CPB did not induce any significant changes in HRV or hemodynamics.

Effects of Percutaneous Stimulation of Both Sympathetic and Parasympathetic Cardiac Autonomic Nerves on Cardiac Function in Dogs

Augmentation of left ventricular (LV) contractility and heart rate (HR) by sympathetic nerve stimulation and amelioration of heart failure by vagal nerve stimulation has been reported. However, the effects of concomitant electrical stimulation of both sympathetic and parasympathetic cardiac nerves in tissues such as those of the cardiac plexus remain unclear. This study sought to assess acute changes in cardiac function and hemodynamics in response to endovascular cardiac plexus stimulation (CPS). Twelve dogs received endovascular CPS via a bipolar catheter within the right pulmonary artery. Stimulation frequency (20 Hz) and pulse width (4 milliseconds) were fixed; voltage varied (range, 15-60 V). Results fell into three categories: 1, no response (n = 4); 2, an increase in systemic arterial pressure that was dependent on electrode placement (n = 4); and 3, a very reproducible and stable increase in aortic pressure (n = 4). In the third group, mean systolic aortic pressures, maximum value of the first derivative of LV pressure, and LV stroke work increased with stimulation (P < 0.02 for all parameters) as did cardiac output, end-systolic elastance, and preload recruitable stroke work (P = 0.03). Systemic and pulmonary vascular resistance, central venous pressure, pulmonary arterial pressure, and HR remained unchanged (P > 0.05). In contrast to conventional inotropic agents, endovascular CPS induced significant and selective increases in LV contractility without increasing HR. Efforts to optimize electrode placement and fixation will improve the reproducibility of endovascular CPS treatment.

Inhibition of AT1 receptors alters remodeling of the guinea pig cardiac plexus following chronic MI

Chronic heart disease induces remodeling in the guinea pig intrinsic cardiac plexus, which includes changes in responses to Angiotensin II (Ang II). We examined the role of Ang II in the remodeling process by using chronic treatment with either an AT1 antagonist (Losartan, 3mg/kg/day) or an ACE inhibitor (captopril, 3mg/kg/day) for 6 weeks following surgically‐induced myocardial infarction (MI). Intracellular voltage recordings from individual intracardiac neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Losartan and captopril treatments inhibited the synergistic effects of Ang II on the increase in neuronal excitability with either adrenergic or muscarinic agonists in MI, but did not alter the increase in excitability produced by adrenergic agonists alone. Losartan treatment increased synaptic efficacy for intracardiac neurons in MI animals; captopril did not. These results suggest that Ang II modulates neuronal remodeling post‐MI and that stimulation of AT1 receptors may be involved in the modulation of functional responses in the intrinsic cardiac plexus in the diseased heart.

Radiofrequency catheter ablation of pulmonary vein roots results in axonal degeneration of distal epicardial nerves

BackgroundIn treatment of atrial fibrillations (AF), radiofrequency ablation (RFA) at the pulmonary vein (PV) roots isolates AF triggers in the myocardial sleeves, but also can destroy PV ganglia and branches of the intrinsic cardiac nerve plexus. AimTo determine the long-term impact of RFA at the PV roots on the structure of epicardial nerves located distally from the RFA site. MethodsFive black-faced sheep underwent epicardial RFA of the left and middle PV roots. Two to 3months after RFA, we obtained samples of epicardial nerves from remote locations of the left dorsal (LD) neural subplexus that extends along the roots of the superior PVs toward the coronary sinus (CS) and dorsal left ventricle (LV). Right atrial epicardial nerves from the right ventral (RV) neural subplexus of the ablated animals and epicardial nerves from LD neural subplexus of five additional intact sheep were used as control. Nerve morphology was examined using histochemical, immunohistochemical and transmission electron microscopy. ResultsHistochemical acetylcholinesterase staining did not reveal any epicardial nerve alterations. However, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) staining showed clearly the reduced numbers of TH and ChAT immunoreactive (IR) nerve fibers within epicardial nerves derived from the remote LD subplexus; control samples from all examined animals were full of evenly distributed TH-IR and ChAT-IR nerve fibers. In sharp contrast to control nerves, numerous swollen or disintegrated axons and Schwann cells with pyknotic nuclei inside unmyelinated and myelinated nerve fibers were identified by electron microscopy of ultrathin sections of epicardial nerves from the CS and LV regions in all ablated animals. ConclusionsDegeneration of remote atrial and ventricular epicardial nerves is evident 2–3months after epicardial RFA at the PV roots. Such nerves are likely to be non-functional. Therefore, long-term autonomic dysfunction is a potential risk of PV isolation by RFA.

Detailed Comparative Anatomy of the Extrinsic Cardiac Nerve Plexus and Postnatal Reorganization of the Cardiac Position and Innervation in the Great Apes: Orangutans, Gorillas, and Chimpanzees

To speculate how the extrinsic cardiac nerve plexus (ECNP) evolves phyletically and ontogenetically within the primate lineage, we conducted a comparative anatomical study of the ECNP, including an imaging examination in the great apes using 20 sides from 11 bodies from three species and a range of postnatal stages from newborns to mature adults. Although the position of the middle cervical ganglion (MG) in the great apes tended to be relatively lower than that in humans, the morphology of the ECNP in adult great apes was almost consistent with that in adult humans but essentially different from that in the lesser apes or gibbons. Therefore, the well-argued anatomical question of when did the MG acquire communicating branches with the spinal cervical nerves and appear constantly in all sympathetic cardiac nerves during primate evolution is clearly considered to be after the great apes and gibbons split. Moreover, a horizontal four-chambered heart and a lifted cardiac apex with a relatively large volume in newborn great apes rapidly changed its position downward, as seen in humans during postnatal growth and was associated with a reduction in the hepatic volume by imaging diagnosis and gross anatomy. In addition, our observation using a range of postnatal stages exhibits that two sympathetic ganglia, the middle cervical and cervicothoracic ganglia, differed between the early and later postnatal stages.

An in vivo map of bone morphogenetic protein 2 post‐transcriptional repression in the heart

The Bmp2 3'untranslated region (UTR) sequence bears a sequence conserved between mammals and fishes that can post-transcriptionally activate or repress protein synthesis. We developed a map of embryonic cells in the mouse where this potent Bmp2 regulatory sequence functions by using a lacZ reporter transgene with a 3'UTR bearing two loxP sites flanking the ultra-conserved sequence. Cre-recombinase-mediated deletion of the ultra-conserved sequence caused strong ectopic expression in proepicardium, epicardium and epicardium-derived cells (EPDC) and in tissues with known epicardial contributions (coronary vessels and valves). Transient transfections of reporters in the epicardial/mesothelial cell (EMC) line confirmed this repression. Ectopic expression of the recombined transgene also occurred in the aorta, outlet septum, posterior cardiac plexus, cardiac and extracardiac nerves and neural ganglia. Bmp2 is dynamically regulated in the developing heart. 3'UTR-mediated mechanisms that restrain BMP2 synthesis may be relevant to congenital heart and vasculature malformations and to adult diseases involving aberrant BMP2 synthesis.

Angiotensin II potentiates adrenergic and muscarinic modulation of guinea pig intracardiac neurons

The intrinsic cardiac plexus represents a major peripheral integration site for neuronal, hormonal, and locally produced neuromodulators controlling efferent neuronal output to the heart. This study examined the interdependence of norepinephrine, muscarinic agonists, and ANG II, to modulate intrinsic cardiac neuronal activity. Intracellular voltage recordings from whole-mount preparations of the guinea pig cardiac plexus were used to determine changes in active and passive electrical properties of individual intrinsic cardiac neurons. Application of either adrenergic or muscarinic agonists induced changes in neuronal resting membrane potentials, decreased afterhyperpolarization duration of single action potentials, and increased neuronal excitability. Adrenergic responses were inhibited by removal of extracellular calcium ions, while muscarinic responses were inhibited by application of TEA. The adrenergic responses were heterogeneous, responding to a variety of receptor-specific agonists (phenylephrine, clonidine, dobutamine, and terbutaline), although α-receptor agonists produced the most frequent responses. Application of ANG II alone produced a significant increase in excitability, while application of ANG II in combination with either adrenergic or muscarinic agonists produced a much larger potentiation of excitability. The ANG II-induced modulation of firing was blocked by the angiotensin type 2 (AT(2)) receptor inhibitor PD 123319 and was mimicked by the AT(2) receptor agonist CGP-42112A. AT(1) receptor blockade with telmasartin did not alter neuronal responses to ANG II. These data demonstrate that ANG II potentiates both muscarinically and adrenergically mediated activation of intrinsic cardiac neurons, doing so primarily via AT(2) receptor-dependent mechanisms. These neurohumoral interactions may be fundamental to regulation of neuronal excitability within the intrinsic cardiac nervous system.

Physiology of the intrinsic cardiac nervous system

The article entitled “Immunohistochemical characterization of the intrinsic cardiac neural plexus in whole-mount mouse heart preparations” by Rysevaite et al1 in this issue of Heart Rhythm depicts the locations of ganglia and interconnecting nerve trunks within the heart of a small mammalian model—that of the mouse. The authors also have characterized a few of the neurochemicals therein, ones that are known to be associated with somata and axons of the mammalian intrinsic cardiac nervous system.

Immunohistochemical characterization of the intrinsic cardiac neural plexus in whole-mount mouse heart preparations

The intrinsic neural plexus of the mouse heart has not been adequately investigated despite the extensive use of this species in experimental cardiology. The purpose of this study was to determine the distribution of cholinergic, adrenergic, and sensory neural components in whole-mount mouse heart preparations using double immunohistochemical labeling. Intrinsic neurons were concentrated within 19 ± 3 ganglia (n = 20 mice) of varying size, scattered on the medial side of the inferior caval (caudal) vein on the right atrium and close to the pulmonary veins on the left atrium. Of a total of 1,082 ± 160 neurons, most somata (83%) were choline acetyltransferase (ChAT) immunoreactive, whereas 4% were tyrosine hydroxylase (TH) immunoreactive; 14% of ganglionic cells were biphenotypic for ChAT and TH. The most intense ChAT staining was observed in axonal varicosities. ChAT was evident in nerve fibers interconnecting intrinsic ganglia. Both ChAT and TH immunoreactivity were abundant within the nerves accessing the heart. However, epicardial TH-immunoreactive nerve fibers were predominant on the dorsal and ventral left atrium, whereas most ChAT-positive axons proceeded on the heart base toward the large intrinsic ganglia and on the epicardium of the root of the right cranial vein. Substance P-positive and calcitonin gene-related peptide-immunoreactive nerve fibers were abundant on the epicardium and within ganglia adjacent to the heart hilum. Small intensely fluorescent cells were grouped into clusters of 3 to 8 and were dispersed within large ganglia or separately on the atrial and ventricular walls. Although some nerves and neuronal bundles of the mouse epicardial plexus are mixed, most express either adrenergic or cholinergic markers. Therefore, selective stimulation and/or ablation of the functionally distinct intrinsic neural pathways should allow the study of specific effects on cardiac function.

Morphologic pattern of the intrinsic ganglionated nerve plexus in mouse heart

Both normal and genetically modified mice are excellent models for investigating molecular mechanisms of arrhythmogenic cardiac diseases that may be associated with an imbalance between sympathetic and parasympathetic nervous input to the heart. The purpose of this study was to (1) determine the structural organization of the mouse cardiac neural plexus, (2) identify extrinsic neural sources and their relationship with the cardiac plexus, and (3) reveal any anatomic differences in the cardiac plexus between mouse and other species. Cardiac nerve structures were visualized using histochemical staining for acetylcholinesterase (AChE) on whole heart and thorax-dissected preparations derived from 25 mice. To confirm the reliability of staining parasympathetic and sympathetic neural components in the mouse heart, we applied a histochemical method for AChE and immunohistochemistry for tyrosine hydroxylase (TH) and/or choline acetyltransferase (ChAT) on whole mounts preparations from six mice. Double immunohistochemical labeling of TH and ChAT on AChE-positive neural elements in mouse whole mounts demonstrated equal staining of nerves and ganglia for AChE that were positive for both TH and ChAT. The extrinsic cardiac nerves access the mouse heart at the right and left cranial veins and interblend within the ganglionated nerve plexus of the heart hilum that is persistently localized on the heart base. Nerves and bundles of nerve fibers extend epicardially from this plexus to atria and ventricles by left dorsal, dorsal right atrial, right ventral, and ventral left atrial routes or subplexuses. The right cranial vein receives extrinsic nerves that mainly originate from the right cervicothoracic ganglion and a branch of the right vagus nerve, whereas the left cranial vein is supplied by extrinsic nerves from the left cervicothoracic ganglion and the left vagus nerve. The majority of intrinsic cardiac ganglia are localized on the heart base at the roots of the pulmonary veins. These ganglia are interlinked by interganglionic nerves into the above mentioned nerve plexus of the heart hilum. In general, the examined hearts contained 19 ± 3 ganglia, giving a cumulative ganglion area of 0.4 ± 0.1 mm(2). Despite substantial anatomic differences in ganglion number and distribution, the structural organization of the intrinsic ganglionated plexus in the mouse heart corresponds in general to that of other mammalian species, including human.

Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain

Involvement of the peripheral nervous system (PNS) is relatively common in some neurodegenerative proteinopathies of the brain and may be pathogenetically and diagnostically important. In Parkinson's disease, neuronal alpha-synuclein aggregates are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. The pathological process may target the PNS and CNS at the same time. In multiple system atrophy, numerous glial cytoplasmic inclusions composed of filamentous alpha-synuclein are widely distributed in the CNS, while alpha-synuclein accumulation is minimal in the sympathetic ganglia and is restricted to neurons. Neurofibrillary tangles can occur in the sympathetic and spinal ganglia in tauopathy, although they appear to develop independently of cerebral Alzheimer's disease pathology. In amyotrophic lateral sclerosis, neuronal loss with TDP-43-positive neuronal cytoplasmic inclusions in the spinal ganglia is more frequent than previously thought. Peripheral ganglia and visceral organs are also involved in polyglutamine diseases. Further elucidation and characterization of PNS lesions will have implications for intravital biopsy diagnosis in neurodegenerative proteinopathy, particularly in Parkinson's disease.

Parasympathetic cholinergic transmission, minus the vesicles

Our understanding of quantal transmission developed initially through the skeletal neuromuscular junction (Fatt & Katz, 1952), and it took about 30 years for a similar phenomenon to be confirmed in autonomic nerves (Blakeley & Cunnane, 1979; Hirst & Neild, 1980). The first convincing demonstration of non-quantal release of acetylcholine at the neuromuscular junction occurred about 30 years ago (Katz & Miledi, 1977), and it is only now, in this issue of Experimental Physiology, that similar effects are shown for parasympathetic junctions (Abramochkin et al. 2009). One problem hampering the study of parasympathetic nerve terminals is their diffuse innervation, forming complex and irregular three-dimensional networks amidst other cells types. The electrical coupling between smooth and cardiac muscles in situ makes the interpretation of electrophysiological experiments more complex, while the presence of G-protein-coupled receptors (such as muscarinic receptors) on parasympathetic targets rather than ligand-gated ion channels (such as nicotinic receptors) makes the detection of neurotransmitter release inherently less sensitive. Abramochkin and colleagues (2009) show that when acetylcholinesterase is pharmacologically inhibited, several cardiac parameters (including heart rate) are sensitive to the muscarinic receptor antagonist, atropine. This suggests that there is tonic release of a cholinergic agonist, almost certainly acetylcholine, from within the atria that persists when vesicular release is prevented with botulinum toxin. Further evidence that acetylcholine itself is involved comes from experiments with hemicholinium III, which inhibits choline transport into the nerve terminals, hence preventing local acetylcholine production and reducing the atropine-sensitive effects. The effectiveness of the botulinum-toxin-induced inhibition of vesicular release was elegantly demonstrated using a fluorescent indicator of vesicle cycling, FM1-43. One of the anticholinesterases used, armin, has a contentious geopolitical history, but its use is not critical for the interpretation of the study because of the additional use of hexamethonium. The relative contributions of non-quantal and quantal transmitter release from parasympathetic nerves in normal conditions still need to be established, although such ratios do not necessarily reflect their relative importance. For example, at the skeletal neuromuscular junction the non-quantal leak of acetylcholine may be two orders of magnitude higher than the quantal release associated with the endplate potentials (reviewed by Katz & Miledi, 1977), yet the importance of quantal transmission for skeletal muscle contraction can be seen in the effectiveness of botulinum toxin for relaxing skeletal muscle, for which it is commonly used in general anaesthesia and therapeutically, to manage muscles that spasm. Botulinum toxin is also useful for treating some smooth muscles that spasm, such as in the oesophagus (achalasia) or in the overactive bladder; in both cases, botulinum toxin is an effective yet temporary treatment that causes the muscles to relax because they are no longer driven by the quantal (or packeted and vesicular) release of acetylcholine. Could non-quantal acetylcholine release be important outside the heart? Perhaps, but the pleomorphism and functional diversity of autonomic targets makes generalization difficult. It is worth considering whether separate targeting of non-vesicular acetylcholine release might have some therapeutic benefit. So far, functional effects of such release have only been shown in the presence of acetylcholinestase inhibition, so as yet there is no evidence for an important role in normal cardiac physiology. However, acetylcholinesterase inhibitors are not infrequently given, in the context of reversing non-depolarizing neuromuscular blocking drugs or for myasthenia gravis, so it may be that during such pharmacotherapy non-vesicular acetylcholine release has some acute cardiac effects. Abramochkin et al. (2009) suggest that a low concentration of acetylcholine released from the parasympathetic nerves may be trophic or anti-apoptotic, both reasonable and testable hypotheses. For all of the very elegant studies presented by Abramochkin et al. (2009), the non-vesicular release of acetylcholine still needs further investigation. For example, to be sure that acetycholine was the cholinergic agonist activating muscarinic receptors it would be helpful to assay acetylcholine more directly, but the required sensitivity (while maintaining specificity) is difficult to achieve. Non-neuronal sources of acetylcholine (for a review, see Kawashima & Fujii, 2008) might also play a role. While Abramochkin et al. (2009) wisely block ganglionic transmission in their model system, it would be interesting to explore the role of non-vesicular acetylcholine release in the cardiac intrinsic plexus, an understudied network that should be capable of significant information processing and signalling. Let us hope that research into autonomic junctions does not continue to lag 30 years behind its somatic cousin.

Intrinsic neural reflexes in the post-transplant human heart

Radiofrequency ablation of post-transplant flutter in a centrally denervated donor atrium at a site remote from the AV node resulted in transient worsening of AV nodal conduction, with absent central vagal reinnervation. This could be an electrophysiological marker of intact innervation to the donor AV node from the intrinsic cardiac neuronal plexus, not demonstrated in human hearts earlier.

Remodeling of the guinea pig intrinsic cardiac plexus with chronic pressure overload

Chronic pressure overload (PO) is associated with cardiac hypertrophy and altered autonomic control of cardiac function, in which the latter may involve adaptations in central and/or peripheral cardiac neural control mechanisms. To evaluate the specific remodeling of the intrinsic cardiac nervous system following pressure overload, the descending thoracic aorta artery of the guinea pig was constricted approximately 20%, and the animals recovered for 9 wk. Thereafter, atrial neurons of the intrinsic cardiac plexus were isolated for electrophysiological and immunohistochemical analyses. Intracellular voltage recordings from intrinsic cardiac neurons demonstrated no significant changes in passive membrane properties or action potential depolarization compared with age-matched controls and sham-operated animals, but afterhyperpolarization duration was increased in PO animals. Neuronal excitability, as determined by the number of action potentials produced with depolarizing stimuli, was differentially increased in phasic neurons derived from PO animals in response to exogenously applied histamine compared with sham and age-matched controls. Conversely, pituitary adenylate cyclase-activating polypeptide-induced increases in intrinsic cardiac neuron evoked AP frequency were similar between control and PO animals. Immunohistochemical analysis demonstrated a twofold increase in the percentage of neurons immunoreactive for neuronal nitric oxide synthase in PO animals compared with control. The density of mast cells within the intrinsic cardiac plexus from PO animals was also increased twofold compared with preparations from control animals. These results indicate that congestive heart failure associated with chronic pressure overload induces a differential remodeling of intrinsic cardiac neurons and upregulation of neuronal responsiveness to specific neuromodulators.

Targeting of cardiac autonomic plexus for modulation of intracardiac neural tone

Ventricular rate control is considered as an initial choice of therapy in many patients with atrial fibrillation (AF). We could previously show that electrostimulation of the right inferior ganglionated plexus (RIGP), which supplies the AV node, instantly decreases ventricular rate during AF. This study describes the development of a technique to reliably implant a chronic lead inside the RIGP. In nine mongrel dogs with AF, the RIGP was identified by neuromapping with probatory high-frequency stimulation (20 Hz) over steerable electrode catheters until a significant ventricular rate slowing was achieved. Then an active fixation, permanent pacemaker lead was fixed closed to the mapping catheter left in place as anatomical marker. Initially (n = 4) available guiding catheters and steerable lead stylets were employed to navigate and anchor the lead, which resulted in repetitive screw-in attempts. Therefore, a guiding catheter was developed, which allowed angiography, lead advancement through its lumen, and probatory neurostimulation over its tip. This tool allowed lead delivery within 40 min (n = 5). Neurostimulation via the permanent lead elicited negative dromotropic effects with stimulation frequency, voltage, and impulse duration as determinants of stimulation efficacy. Active fixation of a permanent pacing lead inside the RIGP is feasible without thoracotomy. Thereby, ventricular rate control during AF can be achieved with stimulus voltages applied for myocardial electrostimulation.

Chronic myocardial infarction induces phenotypic and functional remodeling in the guinea pig cardiac plexus

Chronic myocardial infarction (CMI) is associated with remodeling of the ventricle and evokes adaption in the cardiac neurohumoral control systems. To evaluate the remodeling of the intrinsic cardiac nervous system following myocardial infarction, the dorsal descending coronary artery was ligated in the guinea pig heart and the animals were allowed to recover for 7-9 wk. Thereafter, atrial neurons of the intrinsic cardiac plexus were isolated for electrophysiological and immunohistochemical analyses. Intracellular voltage recordings from intrinsic cardiac neurons demonstrated no significant changes in passive membrane properties or action potential configuration compared with age-matched controls and sham-operated animals. The intrinsic cardiac neurons from chronic infarcted hearts did demonstrate an increase in evoked action potential (AP) frequency (as determined by the number of APs produced with depolarizing stimuli) and an increase in responses to exogenously applied histamine compared with sham and age-matched controls. Conversely, pituitary adenylate cyclase-activating polypeptide (PACAP)-induced increases in intrinsic cardiac neuron-evoked AP frequency were similar between control and CMI animals. Immunohistochemical analysis demonstrated a threefold increase in percentage of neurons immunoreactive for neuronal nitric oxide synthase (NOS) in CMI animals compared with control and the additional expression of inducible NOS by some neurons, which was not evident in control animals. Finally, the density of mast cells within the intrinsic cardiac plexus was increased threefold in preparations from CMI animals. These results indicate that CMI induces a differential remodeling of intrinsic cardiac neurons and functional upregulation of neuronal responsiveness to specific neuromodulators.